Effect of Decrease in Both Postprandial Blood Glucose (PBG) and Fasting Blood Glucose (FBG) Levels in Normal Beagle Dogs with Nateglinide Enteric Coated Granules and Immediate Release Tablets

Abstract

Ordinary antidiabetics for oral administration are classified into two types. The first type primarily controls postprandial blood glucose level (PBG), while the other type primarily controls fasting blood glucose level (FBG). 1,2) There is currently no oral antidiabetic capable of controlling both PBG and FBG, and such an antidiabetic is believed to be the most useful for the treatment of diabetes.The D-phenylalanine derivative, nateglinide ((Ϫ)-N-(trans-4-isopropylcyclohexanecarbonyl)-D-phenylalanine) was developed by Ajinomoto for use as an antidiabetic (Fig. 1). Although nateglinide stimulates insulin secretion, it has a different chemical structure from sulfonylureas, 1,3) demonstrates a quick action/short duration type effect, 1,2,4) and its effect is believed to effectively control primarily PBG. Since blood glucose level inhibitory effects dissipate in a short period of time, nateglinide is expected to realize (1) avoidance of a hypoglycemic state, and (2) avoidance of b cell exhaustion following long-term administration and avoidance of secondary failure.1) Nateglinide immediate release (IR) tablets are currently available commercially in the form of Fastic ® tablets, and are used primarily for patients with mild diabetes. On the other hand, it is important to control FBG in patients with moderate and severe diabetes who exhibit elevated FBG levels. If the nateglinide oral controlled release formulation were available that is capable of controlling both PBG and FBG, it could be expected to offer the advantages of (1) improving compliance by reducing the number of administrations per day (Fastic ® tablets: 3 times per day), and (2) increasing the number of choices available for treating diabetes in moderate and severe diabetes patients.Gliclazide is an antidiabetic that is a long acting type stimulator of insulin secretion having a sulfonylurea moiety. In the case of repeated administration of gliclazide to normal rats, the blood glucose lowering action has been reported to weaken during the second administration. 5) Nateglinide is also an insulin secretion stimulator. Consequently, in the case of designing a controlled release formulation that contains nateglinide for the purpose of effectively inhibiting both PBG and FBG, there have been concerns that even if it is Nateglinide is a new quick action/short duration (QRSD) type of oral blood glucose regulator, and nateglinide immediate release tablets are used for patients with mild diabetes under the trade name of Fastic ® tablets. In this study, we attempted to determine if it was possible to control both post-prandial blood glucose level (PBG) and fasting blood glucose level (FBG) for moderate or severe diabetes through controlled release of nateglinide. Enteric coated granules were selected for the administration form for controlled release of nateglinide, and three types of enteric coated granules were prepared having dissolution pH values of 5.5, 6.5 and 7.2. The three types of enteric coated granules were each administered separately or the enteric...

Nateglinide Controlled Release Tablet Containing Compressionable Enteric Coated Granules

“…Therefore, nateglinide In order to decrease FBG with nateglinide, it is necessary to conduct a sustained release of nateglinide. 4) When administering enteric coated granules with meal, it was reported that a sustained release of the drug was achieved. 4,[6][7][8][9][10] Moreover, it was reported that nateglinide was only partially absorbed in the stomach, but was well absorbed in the whole area of the intestines, according to the in situ experiment in rats using a ligated loop method.…”

“…It was thought to be necessary to coat 15 w/w% or more of enteric coating material on core granules to obtain acid resistance. 4) Therefore, 15 w/w% or more of enteric coating materials were coated on the core granules (Enteric Coated Granules (a): 22 w/w% of methacrylic acid copolymer LD (Eudragit ® L30D-55), Enteric Coated Granules (b): 31.4 w/w% of methacrylic acid copolymer LDϩpoly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) (Eudragit ® FS30D) (1 : 9 dry substance weight ratio), Enteric Coated Granules (c): 31.6 w/w% of poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid)). The loss on drying values were 3.6 w/w% (Enteric Coated Granules (a)), 3.4 w/w% (Enteric Coated Granules (b)), 3.2 w/w% (Enteric Coated Granules (c)) respectively.…”

“…The column switching pattern was according to the method described in ref. 4. At a flow rate of 1.0 ml/min, nateglinide eluted in about 7.5 min at 40°C.…”

“…Plasma Nateglinide Concentration 4,5) tube followed by the addition of 0.5 ml of pHϭ6.0 0.05 mol/l phosphate buffer. The mixture was vortex-mixed for 10 s and applied to a Sep-Pak Vac tC18 cartridge that was pre-equilibrated with 5 ml of pHϭ6.0 0.05 mol/l phosphate buffer.…”

“…The amounts of nateglinide in both an immediate release portion and a controlled release portion were decided according to ref. 4 (the immediate release portion: 60 mg of nateglinide, the controlled release portion: 90 mg of nateglinide). The average diameter of used immediate release granules was about 250 mm.…”